1. Field of the Invention
The present invention relates to stabilized forms of choline salicylate, and more particularly to a stable solid choline magnesium salicylate inclusion complex composition which is useful in preparing solid, non-deliquescent pharmaceutical compositions.
2. Description of the Prior Art
Choline salicylate is a well-known analgesic compound having desirable pharmacological and therapeutic properties, as described in U.S. Pat. Nos. 3,069,321 and 3,141,035. The compound, however, possesses an inherent limitation of being highly hygroscopic so that it has been difficult to prepare pharmaceutically acceptable solid dosage forms which are useful for oral administration in the course of choline salicylate therapy of humans and animals. Although crystalline choline salicylate, melting at about 50.degree. C., is known, its hygroscopic properties are such that trace amounts of moisture are sufficient to reduce the crystalline compound to the liquid state and no matter how stringent the effort to remove the absorbed moisture, the product remains in liquid state so that it cannot be used in forming stable solid dosage forms for pharmaceutical use.
The inherent limitations associated with liquid oral dosage forms presents well-known complications in the handling and dispensing of choline salicylate. Liquid preparations require more expensive packaging and special handling since breakage and spillage during shipment are quite common. Another limitation of liquid dosage forms is their difficulty in achieving a palatable, pleasing taste to mask the inherent noxious fishy taste and odor characteristic of choline compounds without use of additional taste masking components.
Various efforts have been made to prepare solid pharmaceutical dosage forms of choline salicylate.
British Patent Specification 708,865 discloses that choline salts are hydroscopic and tend to deliquesce and discolor. These disadvantages are obviated by treating the choline salts with calcium or magnesium oxides or hydroxides, water-soluble calcium or magnesium salts, or difficultly water-soluble or water-insoluble salts of calcium or magnesium with acids which are weaker than the acid contained in the acid choline salt. Specific examples include calcium or magnesium oxides, hydroxides, carbonates, bicarbonates and chlorides of these metals.
U.S. Pat. No. 3,297,529 to BURKE discloses the formation of a loose complex containing choline salicylate and magnesium sulfate which complex may be granulated with conventional excipients and pressed into tablets or encapsulated in gelatin or the like.
In contrast to BURKE, U.S. Pat. No. 3,326,760 to HALPERN discloses converting choline salicylate to a solid compound by reacting with polygalacturonic acid in aqueous alcoholic or hydroalcoholic medium. The resulting solid compound may then be mixed with a granulating aid and a tablet lubricant such as magnesium stearate and formed into tablets.
U.S. Pat. No. 3,759,980 to ROSEN et al. discloses salicylate compounds containing magnesium cation, choline cation and at least one anion selected from salicylic acid anion and acetylsalicylic acid anion. The generic formula of the disclosed compounds consists essentially of the following components:
(R.sub.1,R.sub.2, R.sub.3, R.sub.4, N.sup.+).sub.n (Mg.sup.++).sub.n 1(ArCOO.sup.-).sub.n 2 PA1 (ArCOO.sup.-).sub.n 3(X.sup.-).sub.n 4(H.sub.2 O).sub.n 5
wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are selected from the group consisting of hydrogen, alkyl of 1 to 20 carbon atoms, hydroxyalkyl of 1 to 20 carbon atoms, carboxyalkyl of 1 to 20 carbon atoms and aralkyl of 1 to 20 carbon atoms in the alkyl moiety; Ar and Ar' are an aromatic monocycle or substituted aromatic monocycle; X is sulfate, chloride or substituted carboxylate; n, n.sup.1 and n.sup.2 are integers of at least 1 and n.sup.3, n.sup.4, and n.sup.5 are 0 or an integer of at least 1, provided that when (R.sub.1,R.sub.2,R.sub.3,R.sub.4,N.sup.+).sub.n is choline, (Mg.sup.++).sub.n 1 is magnesium, (ArCOO.sup.-).sub.n 2 is salicylate and n.sup.3 is 0, and (X.sup.-).sub.n 4 is not sulfate. The compounds of ROSEN et al. are produced by mixing an aqueous solution of salicylate, such as choline salicylate, with an aqueous solution of a magnesium salt. Alternatively, ROSEN et al. disclose that a magnesium salt may be added as a solid to an aqueous salicylate solution, and the mixture agitated until the magnesium salt is dissolved to produce a homogeneous solution. According to either disclosed method, the resulting solution is evaporated to the degree of dryness desired, normally 2 to 4% by weight, so that a solid non-deliquescent complex may be obtained and powdered in a mill to the desired particle size.
U.S. Pat. Nos. 3,801,613 and 3,898,332 to SWIMM disclose choline salicylate trimethylsilyl-silicon dioxide compositions and uses thereof. The compound prepared in accordance with these patents is formed when choline salicylate is combined with silanized silicon dioxide under anhydrous conditions. A preferred method of preparing the choline salicylate-silanized silicon dioxide compound involves employing equimolar concentrations of choline chloride and sodium salicylate, suspending the mixture in acetone, mixing and then refluxing for approximately four hours. After cooling and filtering, silanized silicon dioxide, equivalent in weight to the amount of choline salicylate formed, is added to the filtrate and stirred. Subsequently, an equal volume of petroleum ether is added, and the mixture is allowed to stand overnight. Upon removal of the solvent, the formed choline salicylate-silanized silicon dioxide is dried at room temperature under low vacuum until it is free of solvent.
U.S. Pat. No. 3,947,491 KELLY deceased, et al. discloses choline salicylate sulfite and choline salicylate alkali metal sulfite-containing compounds. The disclosed choline salicylate salt-sulfite-complex compound is said to consist of, for example, choline salicylate sodium sulfite, choline salicylate potassium sulfite, or choline salicylate lithium sulfite. The method of preparation involves adding a sulfite-containing compound selected from the group consisting of sodium sulfite, potassium sulfite, and lithium sulfite to an equimolecular quantity of choline salicylate; mixing the same; allowing to stand for at least one-half hour; and recovering the formed choline salicylate salt-sulfite-complex compound.
SWIMM, U.S. Pat. No. 3,965,263, is directed to a method of achieving analgesia in an animal or a human comprising administering to the animal or human a therapeutically sufficient quantity of choline salicylate trimethylsilysilicon-dioxide. The patent also discloses a solid pharmaceutical composition for administering a salicylate-containing compound to an animal or human comprising an amount of 218 mg to 875 mg of choline salicylate trimethylsilysilicon-dioxide and a pharmaceutically acceptable carrier therefor.
KELLY, deceased et al., U.S. Pat. No. 4,001,311, is directed to a choline salicylate sulfite-containing compound selected from choline salicylate sodium bisulfite, choline salicylate sodium metabisulfite, choline salicylate sodium dithionate, choline salicylate sodium hydrosulfite, choline salicylate sodium hyposulfite, choline salicylate potassium bisulfite, choline salicylate potassium metabisulfite, choline salicylate potassium dithionate, choline salicylate potassium hydrosulfite, choline salicylate potassium hyposulfite, choline salicylate lithium bisulfite, choline salicylate lithium metabisulfite, choline salicylate lithium dithionate, choline salicylate lithium hydrosulfite and choline salicylate lithium hyposulfite.
SASMOR, U.S. Pat. No. 4,067,974, discloses the stabilization of choline salicylate in solid form by the addition of a metal salicylate having a valence of at least 2, preferably aluminum, bismuth, calcium or magnesium salicylate. The composition of SASMOR is said to be stabilized to a greater degree by the addition thereto of carboxymethylcellulose. SASMOR alleges that a still greater degree of stabilization is achieved by forming a complex of choline salicylate, metal salicylate and carboxymethylcellulose. This complex is prepared by forming a solution of carboxymethylcellulose, choline salicylate and metal salicylate, allowing the complexing reaction to take place, and subsequently drying.
KELLY, deceased et al., U.S. Pat. No. 4,098,813, is directed to a method for preparing a choline salicylate salt complex compound selected from the group consisting of choline salicylate sodium, potassium and lithium salts of bisulfite, metabisulfite, dithionate, hydrosulfite and hyposulfite. The method involves adding a sulfite containing compound to an equimolecular quantity of choline salicylate; mixing the same; allowing to stand for at least one-half hour and recovering the formed choline salicylate salt complex compound therefrom.
KELLY, deceased et al., U.S. Pat. No. 4,147,776, describes a method of suppressing color formation in a salicylate-containing pharmaceutical formulation which comprises adding between 0.1 to 5.0 percent by weight of a choline salicylate sulfite-containing compound to a salicylate-containing pharmaceutical dosage form, such as a syrup, tablet, gel, or eardrop form of choline salicylate.
HEASLEY, U.S. Pat. No. 4,338,311, discloses solid formulations of choline salicylate and hydrophilic silicon dioxide. The formulation preferably contains from about 35 to 45 parts by weight of hydrophilic silicon dioxide carrier. Formulations containing less than about 25 parts carrier are said to be undesirably hygroscopic and deliquescent. A suitable form of hydrophilic silicon dioxide for use with the disclosed composition includes hydrolyzed silica gel. A preferred method of preparation involves suspending a choline salt in an inert solvent; adding a metal salicylate salt; mixing; cooling the reaction mixture and filtering to remove the inorganic salt; adding an amount of hydrophilic silica to provide a proportion of hydrophilic silicon dioxide to choline salicylate within the specified range; evaporating the residual solvent; and drying the recovered choline salicylate hydrophilic silica formulation.
Despite the foregoing efforts to provide stable, solid formulations of choline salicylate for therapeutic use it appears that no completely satisfactory means for preparing a stable, solid choline salicylate complex is presently available in the art.
Besides the foregoing techniques for preparing solid compositions by reacting liquid choline salicylate with various materials, other procedures have been used to adsorb drugs to enable their delivery in solid dosage forms. While numerous adsorbates have been disclosed, U.S. Pat. No. 3,337,402 to ZENTNER discloses using Veegum to mask the bitter taste of 7-chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2(lH)-one. ZENTNER discloses on column 3, at lines 28 to 44, that 50 to 80 parts by weight of the Veegum (a trademark of R. T. Vanderbelt company for a complex of magnesium aluminum silicate) for each part of drug is preferred to adsorb this drug. In contrast, U.S. Pat. No. 4,761,274 to DENICK et al., discloses the use of magnesium aluminum silicates to adsorb various drugs. The disclosed process involves dissolving the medicament drug in a suitable solvent which is then permitted to sorb into the complex with mixing.